2-Methoxyestradiol, 1,3,5(10)-estratrien-2,3,17β-triol-2-methyl-ether (2-ME2) is an endogenous metabolite of estradiol, the major ovarian estrogen. The chemical formula of 2-ME2 is C19H26O3, and the compound has a molecular weight of 302.4. 2-ME2 has low of estrogenic activity but has been found to have other biological effects.
U.S. Pat. Nos. 5,504,074, 5,661,143, and 5,892,069 to D'Amato et al. disclose methods of treating mammalian diseases characterized by abnormal cell mitosis using 2-ME2. Undesirable cell mitosis is characteristic of many diseases, including, but not limited to, cancer, atherosclerosis, proliferation of solid tumors, vascular malfunctions, endometriosis, retinopathies, arthropathies, and abnormal wound healing. In addition, cell mitosis is important in a wide variety of biological functions, including but not limited to the normal development of the embryo, formation of the corpus luteum, cyclic proliferation of uterine endometrium, wound healing, and inflammatory and immune responses.
U.S. Pat. No. 5,521,168 to Clark discloses using 2-ME2 for lowering intraocular pressure. 2-ME2 also inhibits estrogen-induced pituitary tumor angiogenesis and suppresses tumor growth in Fisher 344 rats as reported by Banerjee, S. K. et al., Proc. Amer. Assoc. Cancer Res. 39, March 1998.
Presently, commercially available preparations of 2-ME2 are either less than 98% pure or contain undesirable steroid contaminants that are of concern for pharmaceutical uses. Important contaminants of these preparations are estradiol, 4-hydroxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol, estrone, and 2-methoxyestrone. The amounts of these contaminants that are found in presently available 2-ME2 preparations are unacceptable for pharmaceutical applications.
Any therapeutic use of 2-ME2 in humans requires 2-ME2 having a high level of purity. In general, therapeutic agents are required to be substantially pure to avoid negative side effects of contaminants. In particular, since 2-ME2 has effects that are counteracted by estradiol and other estrogenic metabolites, it is crucial to have a 2-ME2 preparation substantially free of such contaminants. Effects that may be seen from contaminating estradiol, estrone, and 2-hydroxyestradiol include estrogenic effects such as feminization, endometrial proliferation, increased risk of uterine and breast cancer, developmental effects on sexual organs, inhibition of leukopoesis, and effects on hematopoetic cells. 4-hydroxyestradiol, 4-methoxyestradiol, and estradiol are known mutagens and carcinogens.
Accordingly, what is needed is a composition of 2-ME2 which is greater than 98% pure and which contains substantially no estradiol or other steroids having estrogenic or carcinogenic effects.
What is also needed is a composition containing 2-ME2 that is greater than 99.5% pure.
What is also needed are methods for making 2-ME2 of greater than 98% purity and containing substantially no estradiol or other steroids having estrogenic or carcinogenic effects.
Also needed are methods of substantially separating 2-ME2 from estradiol, related molecules, and other contaminants, resulting in 2-ME2 having a purity of greater than 99.5%.